Cephalosporin derivatives

ABSTRACT

WHEREIN Z is hydrogen, lower alkyl or a salt forming ion and R is aryl, substituted aryl, lower alkyl or cycloalkyl. These compounds are useful as antibacterial agents.   This invention relates to new cephalosporin derivatives and methods for preparing the same, said derivatives having the structure

United States Patent [1 1 Lee [ CEPIIALOSPORIN DERIVATIVES [75] Inventor: Bong Kuk Lee. Old Bridge. NJ.

{73] Assignee: E. R. Squibb & Sons, Inc..

Princeton NJ.

[22] Filed: May 30, I972 I211 @pl. No.: 258,0I5

[52] U.S. Cl 260/240 G; 424/246; 260/243 C [5| Int. Cl C07d 99/24 [58] Field of Search r. 260/242 C, 240 G [56] References Cited UNITED STATES PATENTS 12/1965 Flynn 260/243 C [/1973 Wclch 260/243 C Primary E.\'uminer-Nicholas S. Rizzo Attorney. Agem or Firm-Lawrence S. Levinson; Merle J. Smith; Stephen B Davis [57] ABSTRACT This invention relates to new cephalosporin derivatives and methods for preparing the same, said derivatives having the structure Apr. 29, 1975 ll "1 ext-cam N H ll 0 CH cooz wherein Z is hydrogen. lower alkyl or a salt forming ion and R is aryl, substituted aryl. lower alkyl or cycloalkyl. These compounds are useful as antibacterial agents.

5 Claims. No Drawings CEPHALOSPORIN DERlY-X'llYES This invention relates to new cephalosporin LlCflYlltires of the formula ll '--1 CH-C-NHK N l 7 wherein Y. is l'l \tll'(1gt.ll.l(l\\tl allql or a salt forming ion cg. an alkali metal as sodium or potassium. an alkaline earth metal like calcium or magnesium. or that of an organic base like dibenzylamine. N.l\ldihcnzylethylenediamine or the like. and Q is N=CHR 0r NH-CH2R wherein R is aryl. substituted aryl, lower alkyl or cycoalkyl.

Thus. the cephalosporin derivatives of the invention include the following suli-genuses:

The lower alkyl groups represented by the above R groups include straight or branched chain aliphatic h droearhon radicals having up to seven carbon atoms. such as methyl. ethyl. propyl. isoprop \l lautyl isobutyl. t-hutyl. amyl, hexyl. hept tl. and the like. The lower alkyl groups can include as suhstituents any of the aryl groups mentioned below as Well as halogen (Cl. Br. l or F).

The term ar l" includes monoeyelic or hicyclic monovalent aromatic ring systems such as phenyl or naphthyl. These aryl radicals can include as substituents at the ortho-po ition halogen. hydroxy. alkanoic acid. lower alltoxy amnio or an of the alkyl groups mentioned hereinhel'orc.

For example. ar l radicals and substituted aryl radicals contemplated herein include. but are not limited to, the following:

5. &

and

OCH

The term cycloalkyP includes monocyclic carboeyclic radicals having from 3 to about 6 carbons such as cycloprop rl. eyclobutyl. cyclopentyl and cyclohexyl.

The compounds of Formula ll can he prepared by reacting a compound of the structure with an aldehyde of the structure.

V RCH to form compounds of the structure VI S CH-CNH I l N N ll H CH 0 3 l cooz R In carrying out the above reaction the reaction of compound IV with the aldehyde V is preferably carried out in an aqueous media such as in a mixture of water with a lower alkanol such as methanol ethanol or npropanol. or ketones such as methylethyl ketone or methyl isobutyl ketone. The reaction may be carried at temperatures ranging from about 0 to about 40C. Compound IV is employed in a ratio to Compound V within the range of from about 1:1 to about l:3 preferably from about iii to about 1:15 and optimally at about l:l.l.

Compounds of formula [I can also be prepared by reacting a compound of the formula h ca- 0002 l with an aldehyde of formula V to form a compound of the formula @cacooz N ll VIII

and thereafter reacting VllI with an acid halide compound of the structure Ix xco alkyl to form a mixed anhydride of the structure which is reacted with 7=ADCA tie. Tamino desaceto form the formula ll compounds.

The reaction of Compound Vll with the aldehyde (V) is carried out in the presence of an aqueousalcoholic solvent, such as a mixture of water and meth 5 anol at temperatures ranging from ambient temperature to the boiling point of the solvent, Compound VII can be employed in a molar ratio to the aldehyde (V) within the range of from about l:l to about l:3 and preferably from about 1:1 to about l:l.S.

The reaction of compounds Vlll and IX is carried out in a mixture of solvents such as acetone, dioxane and lutidine at temperatures ranging from about l0 to about 20C and preferably from about l() to about 10C, employing a molar ratio of lX:Vlll within the range of from about lzl to about 3:] preferably l.l:l to 1.511.

The reaction of the mixed anhydride X with 7-ADCA is carried out in an aqueous solvent such as aqueous sodium bicarbonate at a temperature with the range of from about l5 to about 5C and preferably from about 5 to about 0C employing a molar ratio of XzXl within the range of from about 1:08 to about 2:1 and preferably from about l.l:l to about 15:].

Compounds of formula VI can be reduced by reacting VI with a reducing agent such sodium borohydride aluminum borohydride, lithium aluminum hydride or hydrogen in conjunction with a catalyst for reduetion such as platinum or palldium to form com- 30 pounds of the structure III The above reduction can be carried out in water or aqueous solvents, such as aqueous potassium phosphate. at temperatures ranging from about 0 to about 40C and preferably from about 10 to about 20C employing a molar ratio of Compound ll to reducing agent within the range from about l12 to about i and preferably from about l:4 to about lz6.

Alternatively. the formula III compounds can be prepared by forming compounds of formula VI" above, reducing the formula Vlll compound by reacting it with any of the aforementioned reducing agents to form a compound of the formula XII @ sooz l ca ll ll ca-c-o-c-o-alk l l ca which can be reacted with 7-ADCA (formula Xl) to form the formula lIl compounds.

It will be appreciated that essentially the same reaction conditions as set out with respect to the reaction of Compounds Vlll, lX, X and XI, apply here as well.

The starting materials of structure l\/ are prepared by coupling a compound of the structure COOZ herein as starting materials include, but are not limited 7 to, the following and CH0 The products of this invention form salts which are also part of the invention. Basic salts form with the acid moiety as discussed above in connection with the symbol Z. Acid addition salts also form with the a-amino nitrogen. Such acid salts include, for example, inorganic salts such as the hydrohalides, e.g., hydrobromide, hydrochloride, hydroiodide, sulfate, nitrate, phosphate. borate, etc., and organic salts such as acetate, oxalate, tartrate, malate, citrate, succinate, benzo ate. ascorbate. methanesulfonate and the like. It is frequently convenient to isolate and purify the product by forming a soluble or insoluble salt, as desired, then regenerating the free compound, by neutralization, for example.

The compounds of this invention have a broad spectrum of antibacterial activity against both gram positive and gram negative organisms such as Sruphyim'occus aureus, Salmonella scholrmuelleri, Pseudomonas ueruginosu, Proteus i'ulgaris, Escherichia coli and Streptococcus pyogenes. They may be used as antibacterial agents in a prophylactic manner, e.g., in cleaning or disinfecting compositions, or otherwise to combat infections due to organisms such as those named above, and in general may be utilized in a manner similar to penicillin G and other penicillins and cephalosporins. For example, a compound of Formula I or a physiologically acceptable salt thereof may be used in various animal species in an amount of about O.l to mg./kg. daily, orally or parenterally, in single or two to four divided doses to treat infections of bacteria] origin. By way of illustration the PD orally in mice in a single administration is l.3 mg./kg. against Streptococcus. 8.6 mg./kg. against Proteus and 11.8 mg./kg. against Salmonella, respectively. Up to about 600 mg, of a compound of Formula I or a salt thereof may be incorporated in an oral dosage form such as tablets. capsules or elixirs or in an injectable form in a itefile aqueous vehicle prepared according to conventional Pharmaceutical practice. In cleaning or disinfecting compositions, e.g., in barns or dairy equipment. a concentffltlon of about 0.01 to 1% by weight of such compound aumixed with, suspended or dissolved in conventialifli inert dry or aqueous @afiiers for application by waslilflg or spraying may be usd= The following examples are illustrative of the invh= tion. All temperatures are on the Centigrade scale;

EXAMPLE l 7-[2-phenyl-2-[HZ-hydroxy-lnaphthyl)methylenelaminolacetamidol-3-methyl-8- oxo-S-thial-azabicyclo[4.2.0]oct-2-ene'2-carboxylic acid. sodium salt. hydrate A. Na salt of u-aminobenzyl-3-desacet0xy cephalosporin The sodium salt of aaminobenzyl-3-desacetoxy ccphalosporin is formed by dissolving 1.394 mg (4 millimoles) of oz-aminobenzyl-3-desacetoxy cephalosporin and 336 mg (4 millimoles) of NaHCO in a mixture oi 30 ml H- -O and 350 ml methanol.

8. 7-[Z-phcn vl-'l-[ l Z-hydroxy-lnaphthyl lmethylenelamino l-ac :tamido i 3-methyl-2 oxo-i-thia l-azabicyclo[4.2.1)]oct-Z-ene-2-carboxylic acid, sodium salt. hydrate l'er (0.5 M. pH 6). and to this solution is added 325 mg 8.55 millimolesl of NaBH, dissolved in ml H O. dropwise. for 3 hours. with stirring, at a temperature of about lOC. The reaction mixture is acidified to pH 3 in an ice bath. and centrifuged to separate a solid product. After washing the solid twice with 5 ml portions of cold water. it is dried in vacuo. The resulting solid and excess NaHCO, are dissolved in a mixture of it) ml H- .O and 30 ml methanol. The methanol is removed in vacuo A suspension ol the sodium salt of [)laminoiphenylacetic acid 1.75 g lU milltmoles) and Z-hydroxy-l-naphthaldehyde 3.44 g (It) millimolesl in a mixture of ethanol (250 ml) and methanol ml) is refluxed for 2 hours. The mixture is then evaporated under reduced pressure and the residue is washed with ether and recrystallized from ethanol to give the sodiuni salt of phcnyl|l(Z-hydroxy-l-naphthyl)- methylene laminolacetic acid.

2.63 g (8 millimoles) ot' the N-protected amino acid is dissolved in a mixture ol'dry acetone lOt) ml I. did ane I ml) and 2.6 lutidine 1.35 ml). The solution is rapidly chilled to 5. treated with ethyl chlorocarbonate 0.955 mg (0.84 ml. 8.8 millimoles) and stirred at 0 for 10 minutes, during which lutidine hydrochloride is precipitated and the mixed anhydride formed in solution. The suspension is then cooled to -45 and stirred vigorously while an ice-cold solution of 7-ADCA l.3l g (6.1 millimoles) in 392 aqueous sodium bicarbonate (28 ml) is added as rapidly as possible, the temperature of the mixture never being allowed to rise above 0. The resulting solution is stirred for 30 minutes at 0 and then for a further 30 minutes without ctternal cooling. It is then extracted with ether (3 X lSt) ml). only the aqueous phase being retained. The latter is brought to pH 2 by addition oi dilute hydrochloric acid and rapidly extracted with ether lUU ml in 3 portions). These second ether extracts. containing the N-protected cephalosporin. are washed with water t l() ml) and then extracted with sufficient 3% sodium bicarbonate to give a neutral aqueous phase. which is separated and evaporated at low temperature and pressure. The residue is shown, by paper chromatography of a small portion. to contain the sodium salt of the cephalosporin of the above title.

EXAMPLES 4 T012 The procedure described in Example I is repeated with the exception that the aldehyde set out below in Table 1. column A, are employed to thereby form the products set out in column B of Table l at a temperature below 10C to yield the title com- 0 pound. 5

'C-CNH EXAMPLE 3 i T" 'l N a 7-[2 phenyl-2-l[(Z-hydroxy-l- H naphthyl)methylenelamino]-acetamido]-3-methyl-8- CH 0 3 oxo-S-thia-l-azabicyclo[4.2.0] oct-Z-ene-2-carboxylic 5 C002 acid. sodium salt. hydrate R Table I Example Column Column NO. A B

Aldeh de gR-ci-io) Product CH0 s 4 as in column A CHO Table I Continued) Example Column Colunm No. A B

Aldehyde R-CHO! Product CH0 as in column A 7 E- cno CHO 9 1 C I'L' CHO 10 .C H CHO A-CHO EXAMPLES 13 TO 2| Employing the procedure described in Example 2. but substituting as the starting material, the products of Examples 4 to 12. the products set out in Table ll below are obtained.

Table II l c- C--NH S l m: N CH3 2 vllOONa Table II gcontinued) Examgle No R 15 g F 16 w w EXAMPLES 22 To 30 tutmg the starting matena! set out In column A ofTable 45 Ill below, the product shown in column B thereof is ob- Employing the procedure 0f Example 3, but substitu'med.

Start ing Material Product CH-COOZI I I CH-C. NH S i I I N CH 3| 0 1 CH R cooz R v Examgle No. R Z R L as per 22 K column A Table III Continued Examgle No. R Z

' OCH 26 3 H CSHll Na I claim:

1. A compound of the formula:

wherein Q is N=CHR or NHCH R and R is naphthyl or orthosubslituted nuphthyl wherein said substituent is halogen. hydr0xy cnrboxyl, amido, lower alkoxy. or lower alkyl; and Z is hydrogen, lower alkyl, alkali metaL alkaline earth metal, dibenzylamine. or N,N-dibenzylethylenediamine; and acid-addition salts thereof.

3. A compound in accordance with claim 2 wherein Z is Na.

4. A compound in accordance with claim 1 of the for mulu CH2 cooz 5. A compound in accordance with claim 4 wherein Z is Na. 

1. A COMPOUND OF THE FORMULA:
 2. A compound in accordance with claim 1 of the formula
 3. A compound in accordance with claim 2 wherein Z is Na.
 4. A compound in accordance with claim 1 of the formula
 5. A compound in accordance with claim 4 wherein Z is Na. 